Letter | Published:

Atomic-resolution dynamics on the surface of amyloid-β protofibrils probed by solution NMR

Nature volume 480, pages 268272 (08 December 2011) | Download Citation


Exchange dynamics between molecules free in solution and bound to the surface of a large supramolecular structure, a polymer, a membrane or solid support are important in many phenomena in biology and materials science. Here we present a novel and generally applicable solution NMR technique, known as dark-state exchange saturation transfer (DEST), to probe such exchange phenomena with atomic resolution. This is illustrated by the exchange reaction between amyloid-β (Aβ) monomers and polydisperse, NMR-invisible (‘dark’) protofibrils, a process of significant interest because the accumulation of toxic, aggregated forms of Aβ, from small oligomers to very large assemblies, has been implicated in the aetiology of Alzheimer’s disease1,2,3,4,5,6. The 15N-DEST experiment imprints with single-residue-resolution dynamic information on the protofibril-bound species in the form of 15N transverse relaxation rates (15N-R2) and exchange kinetics between monomers and protofibrils onto the easily observed two-dimensional 1H–15N correlation spectrum of the monomer. The exchanging species on the protofibril surface comprise an ensemble of sparsely populated states where each residue is either tethered to (through other residues) or in direct contact with the surface. The first eight residues exist predominantly in a mobile tethered state, whereas the largely hydrophobic central region and part of the carboxy (C)-terminal hydrophobic region are in direct contact with the protofibril surface for a significant proportion of the time. The C-terminal residues of both Aβ40 and Aβ42 display lower affinity for the protofibril surface, indicating that they are likely to be surface exposed rather than buried as in structures of Aβ fibrils7,8,9,10, and might therefore comprise the critical nucleus for fibril formation11,12. The values, however, are significantly larger for the C-terminal residues of Aβ42 than Aβ40, which might explain the former’s higher propensity for rapid aggregation and fibril formation13,14.

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We thank R. Tycko for discussions, D. Baber, D. Garrett and M. Cai for NMR technical assistance, F. Shewmaker for performing dot blots, and W. Qiang, B. Chen and K. Thurber for assistance with atomic force microscopy and electron microscopy imaging. This work was supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health and the AIDS Targeted Antiviral Program of the Office of the Director of the National Institutes of Health (to G.M.C.).

Author information


  1. Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA

    • Nicolas L. Fawzi
    • , Jinfa Ying
    •  & G. Marius Clore
  2. Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA

    • Rodolfo Ghirlando
  3. National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-0520, USA

    • Dennis A. Torchia


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All authors contributed extensively to the work described in this paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to G. Marius Clore.

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